The application proposes a series of projects to extend our current understanding of psychoneuroendocrine abnormalities in PTSD. During the years of the funded project we demonstrated differences between Holocaust survivors with and without PTSD on several neuroendocrine measures. Some of these changes (i.e., low urinary cortisol levels) were similar, but others (i.e., low catecholamine activity) were different than previously observed in other trauma survivors with PTSD. Holocaust survivors afford a unique opportunity to examine enduring effects of catastrophic trauma on neuroendocrine systems in men, and women who are similar in the type, severity, and length of time since trauma, as well as other sociodemographic factors, but who are free of confounds such as comorbid substance abuse, chronic treatment seeking behavior and disability. To better understand the mechanisms underlying the low cortisol and low catecholamine activity that we have recently observed in Holocaust survivors, we will examine the hormonal responses to neuroendocrine challenges and basal plasma neurohormonal release over a 24-hr period in three groups; Holocaust survivors with PTSD; Holocaust survivors without PTSD : and age and demographically comparable individuals who did not experience the Holocaust. We will perform two neuroendocrine challenge tests. The low dose dexamethasone suppression test will be used to evaluate negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA). The metyrapone stimulation test will be used to assess suprapituitary activation of the HPA axis. In both tests, we will characterize lymphocyte glucocorticoid receptor number under basal conditions and in response to dexamethasone and metyrapone administration. We will also characterize tahe circadian rhythm of cortisol, adrenocorticotropin (ACTH), norepinephrine (NE), and MHPG. By comparing the three groups using these paradigms we will be able to differentiate biological abnormalities that are specifically associated with PTSD from those that may be present as a result of trauma exposure, and take a critical step towards elucidating a general pathophysiology for PTSD.